Chronic airway diseases such as chronic bronchitis including COPD and asthma are characterized by inflammation and increased mucus production. Inflammation and excess mucus production are believed to drive the accelerated decline of lung function in chronic airway diseases.
The increased mucus production is attributed to the remodelling of the airway epithelium in which ciliated cells have been replaced by mucus producing goblet cells. The rarification of ciliated cells impairs the mucociliary clearance. Together with the increased mucus production this leads to mucus plugging of the small airways. An important function of mucociliary clearance is to cleanse the airways from inhaled particulates including viruses which have been trapped in the mucus layer and are then removed from the airways together with the mucus through a coordinated movement of the cilia. In airway diseases such as COPD and asthma, the viruses entrapped in mucus and stuck to the airway epithelium encounter good conditions for infection. Viral infections of the lungs in patients with chronic airway diseases result in an exacerbation of the underlying disease, characterized by an aggravation of the symptoms such as excess mucus production, inflammation and airflow limitation. Patients with exacerbations often need to be hospitalized because they suffer from a dramatic reduction of lung function. Further, in the long term, exacerbations lead to a more rapid and more progressive decline of lung functions compared to patients who do not suffer from exacerbations. The major cause of exacerbations are viral infections of the airways and/or lungs.
It has been demonstrated that inhibition of the epidermal growth factor signalling prevents the excess mucus production and increase in goblet cells. Recently it was shown that EGFR inhibitors can also prevent and/or treat viral infections (WO 2005/048928; Liu Kenneth; Gualano Rosa C; Hibbs Margaret L; Anderson Gary P; Bozinovski Steven Epidermal growth factor receptor signaling to Erk1/2 and STATs control the intensity of the epithelial inflammatory responses to rhinovirus infection. The Journal of Biological Chemistry (2008), 283(15), 9977-85; Monick M M. Cameron K. Staber J. Powers L S. Yarovinsky T O. Koland J G. Hunninghake G W. Activation of the epidermal growth factor receptor by respiratory syncytial virus results in increased inflammation and delayed apoptosis. Journal of Biological Chemistry. 280(3):2147-58, 2005).
The present invention relates to the prevention and/or treatment of viral infections and exacerbation in chronic airway diseases such as COPD and asthma. Viral infections can be prevented or treated by EGFR inhibitors either by preventing entry of the virus, by inhibition of virus replication and/or by inhibition of symptoms caused by viral infection. Inhibition of virus entry into the cells and/or replication of the virus will reduce the viral load and reduce the severity and duration of an exacerbation. The inhibition of symptoms caused by viral infection comprises inhibition/reduction of influx of inflammatory cells such as macrophages, neutrophils and lymphocytes, the inhibition of the upregulation of the EGF receptor and EGFR ligand, mucus production and inhibition/alleviation of the severity and duration of exacerbations.
It is the object of the present invention to provide an antiviral agent, i.e. an agent for treating and/or preventing viral infections or for treating and/or preventing exacerbation in chronic airway diseases such as COPD and asthma.